Eicosanoids such as prostaglandin, leukotriene, thromboxane and the like are considered to play an important role in various diseases. In the diseases of, for example, inflammatory diseases such as arteriosclerosis, diabetes, obesity, asthma, rheumatism, osteoarthritis, inflammatory pain and the like, the production pathway of inflammatory eicosanoid is considered to be promoted and involved in the onset and aggravation of the diseases.
As therapeutic drugs for eicosanoid-associated diseases, medicaments such as cyclooxygenase inhibitors, thromboxane A2 receptor antagonists and the like, which suppress production of prostanoids, are clinically applied. However, the need for a prophylactic or therapeutic drug for inflammatory diseases and the like still remains high, and the development of a strong therapeutic drug with less side effects is desired.
Bioorganic & Medicinal Chemistry Letters (2009), 19(17), 5200-5204 (non-patent document 1) discloses that the compounds of the following formula:
and the like are used for the treatment of diseases such as inflammatory disease, multiple sclerosis, psoriasis, rheumatism, rejection of allogeneic transplantation, inflammatory bowel disease and the like as a CXCR3 antagonist.
Synthesis (2007), (23), 3678-3682 (non-patent document 2) reports that the progress of heterocycle synthesis method is important for forming the basis for many pharmaceutically active substances, and discloses the compounds of the following formulas:
and the like.
WO 2007/002701 (patent document 1) discloses that a compound represented by the following formula:
whereinX is a member selected from the group consisting of a bond, —C(O)—, —C(R5)(R6)—, —C(R5)═—S(O)—, —S(O)2— and —N═;Z is a member selected from the group consisting of a bond, —N═, —O—, —S—, —C(R7)═ and —N(R14)—, with the proviso that X and Z are not both a bond;L is a member selected from the group consisting of a bond,C(O)—(C1-C8)alkylene, (C1-C8)alkylene and (C2-C8)heteroalkylene;Q is a member selected from the group consisting of (C1-C8)alkylene, —C(O)—, —OC(O)—, —N(R8)C(O)—, —CH2CO—, —CH2SO— and —CH2SO2—, or L and Q can be optionally bonded together to form a 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms;R1 and R2 are independently a member selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and heteroaryl, or R1 and R2 in combination optionally form a 3 to 8-membered ring having 0 to 2 heteroatoms as ring vertices, orR2 can be optionally bonded to L to form a 5- or 6-membered heterocyclic group having 1 to 4 heteroatoms;R3 is absent or is a member selected from the group consisting of hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, (C1-C20)alkyl, (C2-C8)heteroalkyl, cyclo(C3-C9)heteroalkyl, (C1-C8) acylamino, amidino, guanidino, ureido, cyano, heteroaryl, —CONR9R10 and —CO2R11, or R3 can be optionally bonded to R2 to form a 4-, 5-, 6-, 7- or 8-membered ring having 1 to 3 heteroatoms selected from the group consisting of N, O and S;R4 is a member selected from the group consisting of (C2-C20)alkyl, (C2-C20)heteroalkyl, heteroaryl, aryl, heteroaryl(C1-C6)alkyl, heteroaryl(C2-C6)heteroalkyl, aryl(C1-C6)alkyl and aryl(C2-C6)heteroalkyl;R5 and R6 are independently a member selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)heteroalkyl, heteroaryl and aryl, or R5 and R6 in combination optionally form a 3- to 7-membered ring;R7 and R8 are independently a member selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)heteroalkyl, heteroaryl and aryl;R9, R10 and R11 are independently a member selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)heteroalkyl, heteroaryl, aryl, heteroary(C1-C6)alkyl, heteroaryl(C2-C8)heteroalkyl, aryl(C1-C8)alkyl and aryl(C2-C8)heteroalkyl;Rx, Ry and Rz are independently H, F or cyano, wherein at least one of Rx, Ry and Rz is cyano;Y1 and Y2 are independently a member selected from the group consisting of —C(R12)═, —CH(R12)—, —N═, —O—, —S— and —N(R13)—;Y3 is N or C wherein when Y3 is C, then Y3 shares a double bond with Y2, Y4 or Z;Y4 is N or C wherein when Y4 is C, then Y4 shares a double bond with X, Y1 or Y3;whereineach R12 is a member selected from the group consisting of H, halogen, hydroxy, amino, alkylamino, dialkylamino, (C1-C8)alkyl, cyclo(C3-C6)alkyl, (C2-C8)heteroalkyl, heteroaryl and aryl, or optionally, when Y1 and Y2 are each one of —C(R12)═ or —CH(R12)—, then the two R12 groups in combination can be form a substituted or unsubstituted 5- to 6-membered cycloalkyl, cycloheteroalkyl, aryl or heteroaryl ring, or optionally, when Y1 is —O(R12)═ or —CH(R12)— and X is —C(R5)═ or —C(R5)(R6)—, then R12 and R5 in combination can be form a substituted or unsubstituted 5- to 6-membered cycloalkyl, cycloheteroalkyl, aryl or heteroaryl ring;each R13 is a member selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)heteroalkyl, heteroaryl, aryl, heteroaryl(C1-C6)alkyl, cyclo(C3-C6)alkyl, heteroaryl(C2-C8)heteroalkyl, aryl(C1-C8)alkyl and aryl(C2-C8)heteroalkyl, or optionally, when one of Y1 and Y2 is —C(R12)═ or —CH(R12)— and the other is —N(R13)—, then R12 and R13 in combination can be form a substituted or unsubstituted 5- to 6-membered cycloalkyl, cycloheteroalkyl, aryl or heteroaryl ring, or optionally when Y1 and Y2 are both —N(R13)—, then the two R13 groups in combination can be form a substituted or unsubstituted 5- to 6-membered cycloalkyl, cycloheteroalkyl, aryl or heteroaryl ring; andR14 is a member selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)heteroalkyl, cyclo(C3-C6)alkyl, heteroaryl, aryl, heteroalkyl(C1-C6)alkyl, heteroaryl(C2-C8)heteroalkyl, aryl(C1-C8)alkyl and aryl(C2-C8)heteroalkyl, or optionally, when Y2 is —C(R12)═, —CH(R12)— or —N(R13)—, then R14 or R7 can be bonded to R12 or R13 to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, cycloheteroalkyl, aryl or heteroaryl ring;the ring containing X, Y1, Y2, Y3, Y4 and Z can be aromatic, as will be understood by those of ordinary skill in the art, a salt, a solvate, a prodrug or an isomer is used for the treatment or prophylaxis of particular inflammatory or immunoregulatory disorder or disease, such as asthma, psoriasis, inflammatory bowel disease, allergic disease, rheumatoid arthritis, multiple sclerosis and the like, which are mediated by CXCR3 chemokine receptor.
Arzneimittel Forschung (2006), 56(6), 377-381 (non-patent document 3) discloses that a compound of the following formula:
and the like has a diuretic action.
WO 2005/091711 (patent document 2) discloses that a compound represented by the following formula:
whereinX is O or S;Ar1 and Ar2 are same or different and each is substituted or unsubstituted aryl, 5- to 7-membered heteroaryl or heterocyclyl group; andR1 and R2 are same or different and each is hydrogen, hydroxy, thiol, nitro, formyl, azido, cyano, halo, or substituted or unsubstituted alkyl, haloalkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, acyl, acyloxy, amino, hydrazino, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl or carboxylic acid,or a derivative thereof is used for the treatment of diseases such as rheumatism, osteoporosis, uveitis, acute and chronic myeloid leukemia, atherosclerosis, cancer, pancreatic β cells destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease and the like.
WO 2003/106435 (patent document 3) discloses that a compound represented by the following formula:
wherein:A is C6-C14 aryl or 5- to 7-membered heteroaryl;R1, R2 and R3 are the same or different and each is hydrogen, hydroxyl, nitro, cyano, amino, halogen, carboxy, carbamoyl, mercapto, C1-C6 alkyl, C1-C6 alkyl substituted with from 1 to 7 halogen, C2-C7 alkylcarbonyloxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino (the alkyl groups are the same or different), C2-C7 alkylcarbonylamino, N—(C2-C7 alkylcarbonyl)-N—(C1-C6 alkyl)amino, C2-C7 alkoxycarbonylamino, N—(C2-C7 alkoxycarbonyl)-N—(C1-C6 alkyl)amino, C1-C6 alkylsulfonylamino, N—(C1-C6 alkylsulfonyl)-N—(C1-C6 alkyl)amino, C1-C6 haloalkylsulfonylamino (the C1-C6 haloalkylsulfonylamino is C1-C6 alkylsulfonylamino substituted with from 1 to 7 halogen), N—(C1-C6 haloalkylsulfonyl)-N—(C1-C6 alkyl)amino (the C1-C6 haloalkylsulfonyl is C1-C6 alkylsulfonyl substituted with from 1 to 7 halogen), C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl or di(C1-C6 alkyl)aminocarbonyl (the alkyl groups are the same or different), or R1 and R2 are optionally bonded each other to form C1-C4 alkylenedioxy;R4 and R5 are the same or different and each is hydrogen, hydroxyl, amino, halogen, mercapto, C1-C6 alkyl, C1-C6 alkyl substituted with from 1 to 7 halogen, C1-C6 alkoxy, C2-C7 alkoxycarbonyl or C1-C6 alkylthio;X is hydrogen, hydroxyl, halogen, C1-C6 alkoxy or C1-C6 alkoxy substituted with from 1 to 7 halogen;Y is C1-C6 alkyl, C1-C6 alkyl substituted with from 1 to 7 substituents (the substituents are the same or different and are selected from substituent group α), C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with from 1 to 7 substituents (the substituents are the same or different and are selected from substituent group α), 5- to 9-membered heterocyclyl, 5- to 9-membered heterocyclyl substituted with from 1 to 7 substituents (the substituents are the same or different and are selected from substituent group α), C6-C10 aryl, C6-C10 aryl substituted with from 1 to 4 substituents (the substituents are the same or different and are selected from substituent group β), C4-C14 cycloalkylalkyl, C4-C14 cycloalkylalkyl substituted with from 1 to 7 substituents (the substituents are the same or different and are selected from substituent group α), (5- to 9-membered heterocyclyl)-(C1-C4 alkyl), (5- to 9-membered heterocyclyl)-(C1-C4 alkyl) substituted with from 1 to 7 substituents (the substituents are the same or different and are selected from substituent group α), C7-C14 aralkyl or C7-C14 aralkyl substituted with from 1 to 5 substituents (the substituents are the same or different and are selected from substituent group β);substituent group α is a group consisting of halogen, hydroxyl, cyano, amino, C2-C7 alkylcarbonyloxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, phenyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino (the alkyl groups are the same or different), C2-C7 alkylcarbonylamino, C1-C6 alkylsulfonylamino and C1-C6 haloalkylsulfonylamino (the C1-C6 haloalkylsulfonylamino is C1-C6 alkylsulfonylamino substituted with from 1 to 7 halogen); andsubstituent group β is a group consisting of halogen, hydroxyl, nitro, cyano, amino, C1-C6 alkyl, C1-C6 alkyl substituted with from 1 to 7 halogen atoms, C2-C7 alkylcarbonyloxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino (the alkyl groups are the same or different), C2-C7 alkylcarbonylamino, N—(C2-C7 alkylcarbonyl)-N—(C1-C6 alkyl)amino, C2-C7 alkoxycarbonylamino, N—(C2-C7 alkoxycarbonyl)-N—(C1-C6 alkyl)amino, C1-C6 alkylsulfonylamino, N—(C1-C6 alkylsulfonyl)-N—(C1-C6 alkyl)amino, C1-C6 haloalkylsulfonylamino (the haloalkylsulfonylamino is C1-C6 alkylsulfonylamino substituted with from 1 to 7 halogen), N—(C1-C6 haloalkylsulfonyl)-N—(C1-C6 alkyl)amino (the haloalkylsulfonyl is C1-C6 alkylsulfonyl substituted with from 1 to 7 halogen), C6-C10 aryl, C7-C14 aralkyloxy, C1-C4 alkylenedioxy, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl and di(C1-C6 alkyl)aminocarbonyl (the alkyl are the same or different);provided that when Y is one of the following (i) to (vii), and A is phenyl, then R4 and R5 are both hydrogen and the —C(CF3)2(X) is —C(CF3)2(OH) bonded to the 3- or 4-position on the phenyl group:(i) an alkyl substituted at the 1-position thereof with amino, alkylamino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino or haloalkylsulfonylamino and optionally further substituted at the 1-position thereof with alkyl or phenyl;(ii) cycloalkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino or haloalkylsulfonylamino and optionally further substituted with from 1 to 6 substituents selected from substituent group α;(iii) heterocyclyl having at least one nitrogen atom and optionally substituted with 1 or 2 substituents selected from alkyl, alkylsulfinyl, alkylsulfonyl and phenyl;(iv) cycloalkylalkyl wherein the alkyl moiety is substituted at the 1-position thereof with amino, alkylamino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino or haloalkylsulfonylamino, the cycloalkylalkyl optionally being further substituted with from 1 to 6 substituents selected from substituent group α;(v) heterocyclylalkyl wherein the alkyl moiety is substituted at the 1-position thereof with amino, alkylamino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino or haloalkylsulfonylamino, the heterocyclylalkyl optionally being further substituted with from 1 to 6 substituents selected from substituent group α;(vi) heterocyclylmethyl wherein the heterocyclyl moiety has at least one nitrogen atom and is optionally substituted with from 1 to 7 substituents selected from substituent group α, and the methyl moiety is optionally substituted with alkyl group or phenyl; and(vii) aralkyl group wherein the alkyl moiety is substituted at the 1-position thereof with amino, alkylamino, dialkylamino, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, haloalkylsulfonylamino, N-(alkylcarbonyl)-N-(alkyl)amino, N-(alkoxycarbonyl)-N-(alkyl)amino, N-(alkylsulfonyl)-N-(alkyl)amino or N-(haloalkylsulfonyl)-N-(alkyl)amino, the aralkyl group optionally being further substituted with from 1 to 6 substituents selected from substituent group β, or a salt thereof has anti-arteriosclerosis action and an anti-inflammatory action as a LXR modulator.
Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (2000), 39B (3), 210-214 (non-patent document 4) discloses that a compound the following formula:
and the like has an analgesic action, an antipyretic action, an anti-inflammatory action and a suppressive action of central nervous system.
U.S. Pat. No. 5,925,642 (patent document 4) discloses that a compound represented by the following formula:
whereinR1 is hydrogen or 1-7C-alkyl,R2 is 1-7C-alkyl, phenyl, phenyl-1-4C-alkyl, Ar-1-4C-alkyl, Ar or 1-7C-alkylene substituted by N(R7)R8, wherein Ar is phenyl substituted by R9, R10 and R11,R3 is phenyl or phenyl substituted by R31 and R32, wherein R31 is hydrogen, hydroxyl, halogen, nitro, cyano, carboxyl, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partly fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, amino or mono- or di-1-4C-alkylamino, and R32 is hydrogen, hydroxyl, halogen, nitro, trifluoromethyl, 1-4C-alkyl or 1-4C-alkoxy,R4 is 1-4C-alkyl,A is 1-20C-alkylene or the group A1-X-A2, wherein A1 is 1-17C-alkylene, X is O (oxygen), A2 is 2-18C-alkylene, and the total of the alkylene carbon atoms of A1 and A2 is 19 or less, R5 is Ar1 and R6 is Ar2, orR5 and R6 in combination are methylene substituted by Ar1 and Ar2 [═CH(Ar1)Ar2], orR5 is hydrogen and R6 is methyl substituted by Ar1 and Ar2 [—CH(Ar1)Ar2] or hydroxymethyl substituted by Ar1 and Ar2 [—C(OH)(Ar1)Ar2], wherein Ar1 is phenyl or phenyl substituted by one or two same or different substituents from the group consisting of hydroxyl, halogen, nitro, trifluoromethyl, 1-4C-alkyl and 1-4C-alkoxy, and Ar2 is phenyl or phenyl substituted by one or two same or different substituents from the group consisting of hydroxyl, halogen, 1-4C-alkyl and 1-4C-alkoxy,R7 is 1-7C-alkyl, 3-8C-cycloalkyl, phenyl-1-4C-alkyl or Ar-1-4C-alkyl, andR8 is 1-7C-alkyl, 3-8C-cycloalkyl, phenyl-1-4C-alkyl or Ar-1-4C-alkyl,wherein Ar is phenyl substituted by R9, R10 and R11, or R7 and R8 in combination and including the nitrogen atom which they are bonded to, are an unsubstituted or substituted heterocycle selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, indoline, octahydro-1H-indole, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, decahydroquinoline and decahydroisoquinoline, whereinthe substituted pyrrolidino group is substituted by one or two same or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, hydroxy-1-4C-alkyl, hydroxyl and carboxyl,the substituted piperidino group is substituted by one, two or three same or different substituents selected from the group consisting of 1-4C-alkyl, gem-di-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyl-1-4C-alkyl, hydroxy-1-4C-alkyl, dihydroxy-1-4C-alkyl, di-1-4C-alkylamino, di-1-4C-alkylamino-1-4C-alkyl, pyrrolidino, piperidino, pyrrolidinyl-1-4C-alkyl, piperidyl-1-4C-alkyl, carbamoyl, di-1-4C-alkylaminocarbonyl, piperidinocarbonyl, morpholinocarbonyl, phenyl, phenyl substituted by R9, R10 and R11, phenyl-1-4C-alkyl, benzoyl, benzoyl substituted by halogen, formyl, carboxyl, cyano, hydroxyl, halogen and sulfo,the substituted piperazino group is optionally substituted in the 2-, 3-, 5- or 6-position by a 1-4C-alkyl group, and is substituted in the 4-position by a substituent selected from the group consisting of 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, hydroxy-1-4C-alkyl, di-1-4C-alkylamino-1-4C-alkyl, halo-1-4C-alkyl, carbamoyl, phenyl, phenyl substituted by R9, R10 and R11, phenyl-1-4C-alkyl, phenyl-1-4C-alkyl wherein the phenyl moiety is substituted by R9, R10 and R11, naphthyl, benzhydryl and benzhydryl substituted by halogen,the substituted morpholino group is substituted by one or two same or different 1-4C-alkyl groups,the substituted indolin-1-yl group is optionally substituted in the 2- and/or 3-position by a carboxyl group or by one or two same or different 1-4C-alkyl groups, and the benzo moiety is optionally substituted by one or two same or different substituents selected from the group consisting of 1-4C-alkyl, halogen and nitro,the substituted 1,2,3,4-tetrahydroquinoline group is substituted by one or two same or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl and halogen,the substituted 1,2,3,4-tetrahydroisoquinoline group is optionally substituted in the 1-, 3- and/or 4-positions by one or two same or different substituents selected from the group consisting of 1-4C-alkyl, carboxyl, phenyl, phenyl substituted by R9, R10 and R11, phenyl-1-4C-alkyl and phenyl-1-4C-alkyl wherein the phenyl moiety is substituted by R9, R10 and R11, and the benzo moiety is optionally substituted by one or two substituents selected from the group consisting of hydroxyl, 1-4C-alkoxy and di-1-4C-alkylamino, wherein R9 is hydrogen, hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylcarbonyl, halogen, 1-4C-alkylamino or nitro, R10 is hydrogen, hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, halogen or nitro and R11 is hydrogen or trifluoromethyl,or a salt thereof has a suppressive action of cell proliferation, an antibacterial action and the like.
Journal of the Institution of Chemists (India) (1985), 57(4), 156-158 (non-patent document 5) discloses that a compound of the following formula:
and the like is used for the treatment of neoplastic disease.
However, the present compound is distinguished from any of the above-mentioned compound, and none of the documents discloses that the compound has a delta-5-desaturase inhibitory action.